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Activation of AMPKα1 is essential for regulatory T cell function and autoimmune liver disease prevention

Cellular & Molecular Immunology volume 18, pages 2609–2617 (2021)Cite this article

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Abstract

Regulatory T cells (Treg cells) are crucial for maintaining immune tolerance. Compromising the regulatory function of Treg cells can lead to autoimmune liver disease. However, how Treg cell function is regulated has not been fully clarified. Here, we report that mice with AMP-activated protein kinase alpha 1 (AMPKα1) globally knocked out spontaneously develop immune-mediated liver injury, with massive lymphocyte infiltration in the liver, elevated serum alanine aminotransferase levels, and greater production of autoantibodies. Both transplantation of wild-type bone marrow and adoptive transfer of wild-type Treg cells can prevent liver injury in AMPKα1-KO mice. In addition, Treg cell-specific AMPKα1-KO mice display histological features similar to those associated with autoimmune liver disease, greater production of autoantibodies, and hyperactivation of CD4+ T cells. AMPKα1 deficiency significantly impairs Treg cell suppressive function but does not affect Treg cell differentiation or proliferation. Furthermore, AMPK is activated upon T cell receptor (TCR) stimulation, which triggers Foxp3 phosphorylation, suppressing Foxp3 ubiquitination and proteasomal degradation. Importantly, the frequency of Treg cells and the phosphorylation levels of AMPK at T172 in circulating blood are significantly lower in patients with autoimmune liver diseases. Conclusion: Our data suggest that AMPK maintains the immunosuppressive function of Treg cells and confers protection against autoimmune liver disease.

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Funding

This study was supported in part by the following grants: NHLBI (HL079584, HL080499, HL089920, HL110488, HL128014, and HL132500), NCI (CA213022), NIA (AG047776), NSFC (31870897), and NSFC (81900387). Dr. M.H. Zou is an eminent scholar of the Georgia Research Alliance.

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Author notes

  1. These authors contributed equally: Huaiping Zhu, Zhaoyu Liu, Junqing An.

Authors and Affiliations

  1. The First Affiliated Hospital of USTC, Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China

    Huaiping Zhu

  2. Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, 30303, USA

    Huaiping Zhu, Zhaoyu Liu, Junqing An, Yu Qiu & Ming-Hui Zou

  3. Medical Research Center, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P.R. China

    Zhaoyu Liu

  4. Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA

    Miao Zhang

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  1. Huaiping Zhu
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Contributions

M.-H.Z. conceived the project, H.Z., Z.L., J.A., M.Z., Y.Q. designed the experiments, carried out experiments and analyzed data, Z.L. and H.Z. wrote the manuscript.

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Correspondence to Zhaoyu Liu.

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Zhu, H., Liu, Z., An, J. et al. Activation of AMPKα1 is essential for regulatory T cell function and autoimmune liver disease prevention. Cell Mol Immunol 18, 2609–2617 (2021). https://doi.org/10.1038/s41423-021-00790-w

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